Repetitive
transcranial magnetic
stimulation for
treatment-resistant
major depression
Rapid assessment of other
technologies using the HTA
Core Model
®
for Rapid
Relative Effectiveness
Assessment
Decision Support Document No. 107
ISSN online: 1998-0469
Repetitive
transcranial magnetic
stimulation for
treatment-resistant
major depression
Rapid assessment of other
technologies using the HTA
Core Model
®
for Rapid
Relative Effectiveness
Assessment
Project Team
Project leader: Dr. Katharina Hawlik, MSc Authors: Judit Erdös, MA
Nora Ibargoyen Roteta, MSc, PhD Iñaki Gutiérrez Ibarluzea Project Support
Systematic literature search: Tarquin Mittermayr, BA
External Review: Dr. Emmanuel Haffen, Professor of psychiatry, President of French Association of Biological Psychiatry and Neuropsychopharmacology, Head of laboratory of Neurosciences of the University of Franche-Comté, Head of the Clinical Investigation Centre of the University hospital of Besançon Dr. Dr. Jose Mª Vergara Ugarriza, Head of Neurophysiology of Miguel Servet University Hospital (Zaragoza), Aragon
Internal Review: Lilisbeth Perestelo Perez, MPsych, PhD Amado Rivero-Santana
Nancy Thiry, MSc Dr. Katharina Hawlik, MSc Proof reading: Michal Stanak, MA Factual accuracy check: Neurosoft, Russia
Mag&More GmbH, Germany Correspondence
Judit Erdös, MA. judit.erdos@hta.lbg.ac.at
This report should be referenced as follows:
Erdos J, Ibargoyen-Roteta N, Gutiérrez-Ibarluzea I. Repetitive transcranial magnetic stimulation for treatment-resistant major depression. Decision Support Document No. 107; 2017. Vienna: Ludwig Boltzmann Institute for Health Technology Assessment.
Conflict of interest
All authors and the reviewers involved in the production of this report have declared they have no conflicts of interest in relation to the technology assessed according to according to the EUnetHTA Declaration of interest and confidentiality undertaking of interest (DOICU) statement form.
Disclaimer
The external reviewers did not co-author the scientific report and do not necessarily all agree with its content. Only the LBI-HTA is responsible for errors or omissions that could persist. The final version and the policy recommendations are under the full responsibility of the LBI-HTA.
The HTA Core Model®, developed within EUnetHTA (www.eunethta.eu), has been utilised when producing the contents and/or structure of this work. The following version of the Model was used: HTA Core Model Application for Rapid Relative Effectiveness (REA) Assessments (4.2). Use of the HTA Core Model does not guarantee the accuracy, completeness, quality or usefulness of any information or service produced or provided by using the Model.
Commissioned by the Austrian Ministry of Health, this report systematically assessed the intervention described herein as decision support for the inclusion in the catalogue of benefits.
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Decision support documents of the LBI-HTA do not appear on a regular basis and serve to publicize the research results of the Ludwig Boltzmann Institute of Health Technology Assessments. Decision support documents of the LBI-HTA are only available to the public via the Internet at
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Decision Support Document No.: 107 ISSN-online: 1998-0469
LBI-HTA| 2017 3
Content
Summary
... 9
Zusammenfassung
... 15
1 Scope
... 21
1.1 PICO question ... 21
1.2 Inclusion criteria ... 21
2 Methods and evidence included
... 23
2.1 Research questions ... 23
2.2 Source of assessment elements ... 24
2.3 Search ... 24
2.4 Study selection ... 26
2.4.1 Selection of systematic reviews ... 26
2.4.2 Selection of primary studies ... 27
2.4.3 Selection of guidelines ... 28
2.5 Quality rating of studies ... 28
2.6 Statistical-analysis ... 29
2.7 Description of the evidence ... 30
3 Description and technical characteristics of technology (TEC)
... 33
3.1 Results ... 33
3.1.1 Features of the technology and comparators ... 33
4 Health problem and current use of the technology (CUR)
... 41
4.1 Results ... 41
4.1.1 Overview of the disease or health condition ... 41
4.1.2 Effects of the disease or health condition ... 42
4.1.3 Current clinical management of the disease or health condition ... 43
4.1.4 Target population ... 45
5 Clinical effectiveness (EFF)
... 47
5.1 Results ... 47
5.1.1 Included studies ... 47
5.1.2 Mortality ... 48
5.1.3 Morbidity ... 49
5.1.4 Health-related quality of life ... 57
5.1.5 Satisfaction ... 57
6 Safety (SAF)
... 59
6.1 Results ... 59
6.1.1 Included studies ... 59
6.1.2 Patient safety ... 59
7 Quality of evidence
... 63
8 Discussion
... 67
9 Recommendation
... 71
10 References
... 73
Repetitive transcranial magnetic stimulation for treatment-resistant major depression
4 LBI-HTA | 2017
Appendix 1: Methods and description of the evidence used
... 79
Documentation of the Search Strategies ... 79
Search strategy for SRs ... 79
Search strategy for primary studies ... 82
Description of the evidence used ... 85
Guidelines for diagnosis and management ... 85
Main characteristics of systematic reviews assessed for eligibility ... 90
Evidence tables of individual studies included for clinical effectiveness and safety ... 98
List of ongoing and planned studies ... 118
Risk of bias tables ... 120
Applicability tables ... 121
Appendix 2: Regulatory and reimbursement status
... 122
Appendix 3: Checklist for potential ethical, organizational and legal aspects
... 126
Appendix 4: Diagnostic criteria according to DSM-IV-TR
... 127
Appendix 5: Safety guidelines
...
128
List of tables
Table 1-1: Inclusion criteria ... 21
Table 2-1: Main characteristics of the included systematic review for update ... 30
Table 2-2: Main characteristics of primary studies included in the update: rTMS vs sham... 31
Table 3-1: Features of the intervention ... 35
Table 6-1: Frequency of adverse events in comparative studies ... 61
Table 7-1: Evidence profile: efficacy and safety of rTMS vs sham for TRD ... 64
Table 7-2: Evidence profile: efficacy and safety of rTMS vs ECT for TRD ... 65
Table 9-1: Evidence based recommendations ... 71
Table A-1: Overview of guidelines: diagnosis and management of MDD ... 85
Table A-2: Overview of guidelines focusing on rTMS ... 87
Table A-3: Systematic reviews comparing rTMS with sham rTMS ... 90
Table A-4: Systematic reviews comparing rTMS with ECT ... 95
Table A-5: Characteristics of randomised controlled studies comparing rTMS with sham rTMS ... 98
Table A-6: Characteristics of randomised controlled studies comparing rTMS with ECT ... 114
Table A-7: List of Phase III and IV ongoing studies: sham controlled rTMS trials ... 118
Table A-8: List of Phase III and IV ongoing studies with rTMS compared to other than sham ... 119
Table A-9: Risk of bias – study level (RCTs) ... 120
Table A-10: Summary table characterising the applicability of a body of studies ... 121
Table A-11: Regulatory status ... 122
Table A-12: Summary of reimbursement recommendations in European countries for the technology... 124
Table A-13: Summary of recommendations in European countries for the technology
in the indication under assessment ... 125
Content
LBI-HTA | 2017
5
List of figures
Figure 2-1: Flow chart for selection of systematic reviews ... 26
Figure 2-2: Flow chart for selection of primary studies ... 27
Figure 3-1: Mechanism of action of TMS ... 34
Figure 4-1: Thase-Rush Treatment-Resistant Depression (TRD) Staging Method ... 43
Figure 5-1: Weighted mean difference: rTMS vs sham ... 49
Figure 5-2: Standardized mean difference: rTMS vs sham ... 50
Figure 5-3: Weighted mean difference: rTMS vs ECT ... 51
Figure 5-4: Standardized mean different: rTMS vs ECT ... 51
Figure 5-5: Remission rate at the end of treatment: rTMs vs sham ... 52
Figure 5-6: Risk difference for remission rate: rTMS vs sham ... 53
Figure 5-7: Response rate at the end of treatment: rTMS vs sham ... 54
Figure 5-8: Risk difference for response rate: rTMS vs sham ... 54
Figure 5-9: Remission rate: rTMS vs ECT ... 55
Repetitive transcranial magnetic stimulation for treatment-resistant major depression
6 LBI-HTA | 2017
List of abbreviations
ACROBAT-NRSi ... A Cochrane Risk Of Bias Assessment Tool
for Non-Randomized Studies of Interventions
ADE ... Adverse device effect
AE ... Adverse event
AGREE II ... Advancing guideline development reporting and evaluation in healthcare
AMSTAR ... A Measurement Tool to Assess Systematic Reviews
AOTMiT ... Agencja Oceny Technologii Medycznych i Taryfikacji/
Agency for Health Technology Assessment and pricing
APA ... American Psychiatric Association
aTMS ... Accelerated repetitive transcranial magnetic stimulation
AVALIA-t ... Galician Agency for Health Technology Assessment
B ... Bilateral
BDI ... Beck Depression Inventory
B-rTMS ... Bilateral repetitive transcranial magnetic stimulation
C ... Control
CANMAT ... Canadian Network for Mood and Anxiety Treatments
CBR ... Consensus based recommendation
CE mark ... Conformité Européene
CHIF ... Croatian Health Insurance Fund
CI ... Confidence interval
CPG ... Clinical practice guideline
CRD ... Centre for Research and Dissemination
CST ... Color Stroop Test
DBS ... Deep brain stimulation
DGPPN ... Deutsche Gesellschaft für Psychiatrie und Psychotherapie, Psychosomatik
und Nervenheilkunde/German Association for Psychiatry and Psychotherapy
DLPFC ... Dorsolateral prefrontal cortex
DRG ... Diagnosis-related group
DSM IV-TR ... Diagnostic and statistical manual of mental disorders IV text revision
DTMS ... Deep transcranial magnetic stimulation
EBR ... Evidence-based recommendations
ECT ... Electroconvulsive therapy
EEG ... Electromyography
ETH ... Ethical
EUnetHTA ... European Network of Health Technology Assessment
FDA... Food and Drug Administration
fMRI ... Functional magnetic resonance imaging
FU ... Follow-up
G-BA... Gemeinsamer Bundesausschuss
GRADE ... Grading of Recommendations Assessment, Development and Evaluation
HAS ... French National Authority for Health
H-coil ... Hesed-coil
HDRS/HAMD ... Hamilton Depression Rating Scale
HF ... High-frequency
Content
LBI-HTA | 2017
7
HQO ... Health Quality Ontario
HTA ... Health Technology Assessment
Hz ... Hertz
I ... Intervention
ICD ... International Classification of Diseases
ICTRP ... International Clinical Trials Registry Platform
IFCN ... International Federation of Clinical Neurophysiology
INFARMED ... National Authority of Medicines and Health Products
LBI-HTA ... Ludwig Boltzmann Institute for Health Technology Assessment
LEG ... Legal
LF ... Low-frequency
MA ... Meta-analysis
MADRS ... Montgomery-Asberg Depression Rating Scale
MAOB ... Monoamine oxidase B
MAOI ... Monoamine oxidase inhibitors
MDD ... Major depressive disorder
MDE ... Major depressive episode
MeSH ... Medical Subject Headings
MMSE ... Mini-Mental State Examination
mo ... month
MST ... Magnetic seizure therapy
MT ... Motor threshold
n ... number
N/A ... not available
NAMI ... National Alliance on Mental Illness
NARSAD ... National Alliance for Research on Schizophrenia and Depression
NCCHTA ... National Coordinating Centre for Health Technology Assessment
NHMRC ... National Health and Medical Research Council
NHS... National Health Service
NICE ... National Institute for Health and Clinical Excellence
NIHM ... National Institute of Mental Health
NIJZ ... National Institute of Public Health Slovenia
NIRS ... Near Infrared Spectroscopy
NOS ... Not Otherwise Specified
OGYEI ... Országos Gyógyszerészeti és Élelmezés-egészségügyi Intézet/
National Institute of Pharmacy and Health Products
ORG ... Organizational
OSTEBA ... Basque Office for Health Technology Assessment
PCP ... Phencyclidine
PET ... Positron emission tomography
pts ... patients
QIDS ... Quick Inventory of Depressive Symptomatology
Q-LES-Q ... Quality of Life Enjoyment and Satisfaction Questionnaire
QoL ... Quality of life
Repetitive transcranial magnetic stimulation for treatment-resistant major depression
8 LBI-HTA | 2017
RCT ... Randomized controlled trial
REA ... Relative Effectiveness Assessment
RedAETS ... Red Española de Agencias de Evaluación de Tecnologías Sanitarias
RMT ... Resting motor threshold
RR ... Relative risk
R-rTMS ... Right-side repetitive transcranial magnetic stimulation
rTMS ... Repetitive transcranial magnetic stimulation
SADE ... Serious adverse device effect
SCID ... Structured Clinical Interview for DSM-IV
SD ... Standard deviation
SESCS ... Evaluation Unit of the Canary Islands Health Service
SF 36 PF ... Short Form (36) Health Survey Physical Functioning
SF-36 ... Study-36 Item Short Form
SIGH-SAD ... Structured Interview Guide for the Hamilton Depression Rating Scale
SIGN ... Scottish Intercollegiate Guidelines Network
SMD ... Standardized mean difference
SNRI ... Serotonin–norepinephrine reuptake inhibitors
SOC ... Social
SR ... Systematic review
SSES ... Suicide severity rating scale
SSRI ... Selective serotonin reuptake inhibitors
STAI ... State-Trait Anxiety Inventory
STAR*D ... Sequenced Treatment Alternatives to Relieve Depression
sTMS ... Synchronized transcranial magnetic stimulation
TBS ... Theta Burst Stimulation
TCA ... Tricyclic antidepressants
TDCS ... Transcranial direct current stimulation
TGA ... Therapeutic Goods Administration
TMS ... Transcranial magnetic stimulation
TMT ... Trail Making Test
TRD ... Treatment-resistant depression
UK ... United Kingdom
UMDNS ... Universal Medical Device Nomenclature System
VFT ... Verbal Fluency Test
VNS ... Vagus nerve stimulation
vs ... versus
w ... week
WCST ... Wisconsin Card Sorting Test
WHO ... World Health Organization
WSFBP ... World Federation of Societies of Biological Psychiatry
yrs ... years
LBI-HTA| 2017 9
Summary
Scope
The scope can be found here:
Scope
.
The aim of this report was to assess the effectiveness and safety of repetitive
transcranial magnetic stimulation (rTMS) in treatment-resistant depression
(TRD).
Introduction
Health problem
The target condition in the scope of the assessment is treatment-resistant
major depressive disorder (TRD), which often refers to major depressive
dis-order (MDD) that does not respond satisfactorily to at least two trials of
an-tidepressant monotherapy. However, the definition has not been standardized
yet. Defining treatment resistant depression is also complicated due to the
lack of consensus in describing acute antidepressant responses. In many
stud-ies, response is classified as ≥ 50 percent improvement from baseline on the
depression rating scale. Remission is defined as a depression rating scale score
less than or equal to a specific cut-off that defines the normal range (score on
the HRSD-17 or on the MASD ≤ 7) [1] (A0002).
The prevalence of unipolar TRD is not clear due to the lack of
international-ly acknowledged and standardized definition. However, there are reasonable
estimates available. If response is used as outcome, according to the
defini-tion of response, the prevalence rate for Stage 2 TRD (failure to achieve
re-sponse after two courses of adequate treatment) is estimated to be 15-35% [5,
6, 44] (A0023).
MDD is currently diagnosed by using the Diagnostic Criteria for Major
De-pressive Disorder and DeDe-pressive Episodes (DSM-IV-TR) (details in
Appen-dix 4). Because of differences in treatment, the diagnosis of unipolar MDD
should be confirmed and other diagnosis, such as bipolar depression or
dys-thymic disorder, ruled out. The treatment history of patients who may be
treat-ment resistant is usually assessed through a clinical interview as well as a
re-view of the medical record [1] (A0024).
Description of technology and comparators
Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive
neu-rostimulation and neuromodulation technique, which is delivered as a series
of pulses i.e. a train. The most typical technical parameters of rTMS are the
frequency (high-frequency: stimulation delivered >1 pulse per second, but
generally ≥ 5 Hz is applied as HF [5, 7], or low-frequency: stimulation
de-livered at ≤ 1 pulse per second), intensity (expressed as a percentage of the
resting motor threshold, generally set at 100-120%), train duration, intertrain
interval, number of trains per session, and number of pulses per session [7, 8].
There are various treatment protocols, but the FDA-based standard
parame-ters are most widely used and for the acute treatment they include: 10
mag-netic pulses per second (Hz), 3000 pulses per session, 100 to 120 percent of
motor threshold and train duration of 4 s with intertrain interval of 26 s [9].
However, the stimulation parameters required to optimize the efficacy of
rTMS treatment are not well known.
aim
target population:
patients with TRD
unclear prevalence
diagnosis:
DSM-IV-TR criteria
rTMS: non-invasive
neurostimulation
Technical parameters:
frequency
intensity
train duration
intertrain interval
number of trains
per session
number of pulses
per session
Repetitive transcranial magnetic stimulation for treatment-resistant major depression
10 LBI-HTA | 2017
The use of the rTMS is prohibited for patients with metal implants in the
head area, implanted medical devices during pregnancy, increased
intracra-nial pressure, a history of epileptic seizures, increased cerebral susceptibility
to epileptic seizures through medication and unstable general medical
disor-ders [7, 8, 10] (A0001).
rTMS is indicated for patients with unipolar major depression who have failed
to achieve satisfactory improvement from prior antidepressant medication in
the current episode (A0020). The claimed benefit of rTMS is that it is
non-in-vasive, the patient remains awake and alert throughout the process, no
post-session recovery is needed, hence the patient can resume normal activities
immediately and no cognitive side-effects have been reported with rTMS.
Comparators
Sham stimulation
is delivered with a sham coil.
Electroconvulsive therapy
(ECT) involves the induction of a seizure by the
ap-plication of electrical current to the brain. It is delivered under general
an-aesthesia and application of a muscle relaxant. Treatment parameters include
electrode position, electrical intensity, pulse width and duration [11]. ECT is
a complex intervention and its efficacy and safety are affected by a number
of parameters including the placement of electrodes, dosage and waveform of
the electrical stimulus, and the frequency with which ECT is administered
[12]. As regards to mortality, ECT is a safe procedure with a very low mortality
rate (1 death per 73,440 treatments) [11] (A0001). However, cognitive effects
including transient disorientation when recovering from ECT sessions,
retro-grade and anteroretro-grade amnesia, mild, short-term impairment in memory and
other cognitive domains during and after treatment with ECT might occur.
[4, 11] (B0002).
Methods
The systematic literature search and analysis of the studies was performed in
two phases: secondary studies (i.e. HTA reports and systematic reviews/SRs)
were screened as a first step and evaluated on the basis of their scope,
inclu-sion and excluinclu-sion criteria, and quality. The AMSTAR tool was used for
quali-ty assessment of SRs, and as a result, the Health Qualiquali-ty Ontario (HQO)
re-port [13] was selected for update.
As a second step, to identify further, more recent, primary studies fulfilling
the inclusion criteria of the present assessment, a literature search for
ran-domized controlled trials (RCTs) published since the literature search of the
chosen HQO report [13] was performed. 2 studies [14, 15] were selected that
fulfilled our inclusion criteria and included within the present assessment.
The 2 studies compare HF-rTMS to the left DLPFC with sham. No studies
were found that compared active stimulation with ECT. The Cochrane risk
of bias assessment approach was used to assess the quality of RCTs. For the
assessment of the strength of evidence, the Grading of Recommendations,
Assessment, Development and Evaluation approach was used.
Clinical effectiveness
The critical endpoints in assessing clinical effectiveness were response and
remission rates. The mean difference in depression scores was considered
im-portant, but not critical endpoint.
contraindications
benefits: non-invasive,
no cognitive side-effects,
no general anaesthesia
needed, no post-session
recovery needed
comparators: sham
stimulation
(with a sham coil) …
… and ECT
(neuromodulation
under general
anaesthesia,
induction of a seizure
to the brain)
2-step systematic
literature search:
1. SRs and HTAs
2. RCTs
HQO report selected
for update
Inclusion of additional
2 RCTs
Cochrane risk of bias
tool to assess quality
GRADE approach to
assess the strength of
evidence
critical endpoints:
response and remission
Summary
LBI-HTA | 2017
11
Safety
The critical endpoint in assessing safety was cognitive impairment, whereas
the number of seizures was considered important endpoint.
Results
Available evidence
rTMS vs sham
23 studies met the inclusion criteria in the HQO report. We found two
addi-tional RCTs [14, 15] that are included in the present analysis. One of them
[15] is the 6 month follow-up of a study included in the HQO report [16]. A
total of 1180 patients were analysed in the studies, 615 in the rTMS arm and
565 in the sham arm.
The inclusion criteria of the studies varied as follows:
Baseline values on HDRS-17
In 11 studies: >25 (severe depression)
In 6 studies: 19-24 (moderate depression)
TRD definition
In 16 studies: two or more failed antidepressant trials
In 9 studies: one or more failed antidepressant trial
rTMS as add-on or monotherapy
In 17 studies: add-on therapy
In 8 studies: monotherapy
The stimulation parameters varied: the frequency ranged from 5 to 20 Hz,
the intensity from 80 to 120% of patients’ MT, the number of trains per
ses-sion from 15 to 75, the train duration from 2 to 10 seconds (s), the intertrain
interval from 22 to 58 s, the number of pulses per session from 800 to 3,000,
and the total number of pulses during rTMS treatment from 8,000 to 90,000.
All studies used the figure 8 coil.
rTMS vs ECT
The HQO report included six studies that compared rTMS with ECT. Most
of the studies were conducted in the early 2000s. The total number of patients
was 266, 133 in each arm. Two of the studies reported 6 month follow-up
da-ta as well [17, 18].
The inclusion criteria of the studies varied as follows:
Baseline values on HDRS-17
In the rTMS group: 24-26
In the ECT group: 25-28
TRD definition
In 2 studies: two or more failed antidepressant trials
In 1 study: one or more failed antidepressant trial
In 2 studies the number of failed antidepressant trials was not
re-ported, only the number of failed ECT trials
In 1 study only the number of failed antidepressants in the
cur-rent episode was reported
critical endpoint:
cognitive impairment
25 included studies with
1180 patients
inclusion criteria
varying stimulation
parameters
6 included studies with
266 patients
Repetitive transcranial magnetic stimulation for treatment-resistant major depression
12 LBI-HTA | 2017
rTMS as add-on or monotherapy
In 2 studies: add-on therapy
In 2 studies: monotherapy
In 2 studies: only lorazepam or clonazepam were allowed
The characteristics of the intervention varied also, one study used 20 Hz
fre-quency stimulation, four studies used 10 Hz and one study did not report on
the frequency used. The intensity of the stimulation ranged from 90 to 110%
of the MT, the number of trains from 20 to 30-35, the train duration from 2
to 10 s, the intertrain interval from 20 to 55 s, the pulses per session from 408
to 2500 and the number of sessions from 10 to 20. Hence the total number of
pulses delivered also ranged from 4,080 to 50,000. All studies reported that
they used a figure 8 coil.
Clinical effectiveness
rTMS vs sham
The pooled risk ratio for response rate across 19 studies was 1.82 (95% CI
1.18-2.82; p=.0068). There was a moderate degree of heterogeneity among studies
(I
2=50%, p=.01). This pooled estimate suggests that patients may be twice
more likely to experience treatment response with rTMS than with sham.
The pooled risk ratio for remission rate across 12 studies was 2.16 (95% CI
1.42-3.29; p=.0003). This pooled estimate suggests that patients may be twice
more likely to experience remission with rTMS than with sham. No
hetero-geneity was observed among the studies (I
2=0.0%; p=.7164).
On average, rTMS reduced depression scores by about 2.31 points more than
sham (95% CI 1.19-3.43; p<.001), which is below the mean value that was
deemed a priori clinically important (threshold of 3.5 points).
There was a statistically significant improvement favouring rTMS on the
gen-eral health and mental health SF-36 subscales at 4- and 6-week follow-up.
Statistically significant improvement favouring rTMS was also seen in the
Q-LES-Q total score at 4-and 6-week follow-up [15] (D0012, D0013).
rTMS vs ECT
The pooled risk ratio for response at the end of treatment was 1.72 (95% CI
0.95-3.11, p=.072) favouring ECT. There was a high degree of heterogeneity
among studies (I
2=60.6%, p=.079). While the effect is not statistically
signif-icant, this pooled estimate would suggest a higher response with ECT than
with rTMS (D0006).
The pooled risk ratio for remission was 1.44 (95% CI 0.64-3.23, p=.375) at
the end of treatment, favouring ECT, however, these results are not
signifi-cant. There was a high degree of heterogeneity among studies (I
2=69.1%,
p=.039).
The weighted mean difference of depression scores from baseline to the end
of treatment was -5.97 points (95% CI -11.00 to-0.94, p=.020) in favour of ECT,
which is higher than the mean value that was defined a priori as clinically
important. The degree of heterogeneity among studies was high (I2=72.2%,
p=.013) (D0005).
One study [19] reported data on suicide scores or suicidal ideations. The
su-icide score decreased from 1.5 (0.8) to 1.2 (0.9) as measured by BDI and from
1.9 (1.3) to 1.4 (1.2) as measured by HDRS in the rTMS group. In the ECT
varying stimulation
parameters
RR for response:
1.82 favouring rTMS
RR for remission:
2.16 favouring rTMS
MD 2.31 points
favouring rTMS
significant improvement
favouring rTMS in
general health, mental
health, and Q-LES-Q
RR for response:
1.72 favouring ECT,
but statistically not
significant
RR for remission:
1.44 favouring ECT,
but statistically not
significant
MD 5.97 points
favouring ECT
decrease in suicide
scores greater in the
ECT group
Summary
LBI-HTA | 2017
13
group the decrease was significantly greater: from baseline 1.4 (1.0) to 0.5
(0.7) as measured by BDI and 2.3 (1.1) to 0.3 (0.5) as measured by HDRS
(p<.001). The results suggest that ECT decreases suicidal scores more than
rTMS.
Safety
rTMS vs sham
The most common side-effect presented in the studies was headache. The rate
of headache ranged from 0 to 60% in the rTMS group and from 0 to 50% in
the sham group. Seizures did not occur in any of the studies and transient
impairment of working memory occurred in five patients (16.7%) in the rTMS
group and in one patient (4.3%) in the sham group (C0008).
rTMS vs ECT
No serious safety concerns were identified. The most common side-effect
was headache in rTMS-treated patients. No adverse events occurred in
ECT-treated patients (C0008).
Upcoming evidence
There are four ongoing studies on rTMS compared to sham stimulation, no
ongoing studies comparing rTMS with ECT.
Reimbursement
The technology is not reimbursed in the majority of the countries for which
we have information available (A0021). The reason for its non-inclusion in
the benefit catalogue is either that it has not been assessed or that the
evi-dence is insufficient to issue a recommendation.
Discussion
The overall quality of the body of evidence is very low for both sham and
ECT comparison studies.
The methodological limitations of the studies included in this assessment are
likely to influence the robustness of our findings. These limitations include
variable study parameters (rTMS treatment protocols, the definition of
re-mission, the level of treatment resistance, and if rTMS was used as mono- or
add-on therapy), risk of bias (high risk of bias in the blinding domain in ECT
controlled studies), small sample sizes (in both the sham and ECT controlled
trials).
Ideally, outcomes such as quality of life and function would be primary
out-comes that determine the impact of the intervention, but this was not
re-ported in the included studies, except for one. A major limitation in the
out-comes is that they are not measuring directly the improvement in the
pa-tients’ quality of life and that there is only short-term data available. Patient
satisfaction was also not measured by any dedicated tool.
most common
side-effect: headache
no serious adverse
events
4 ongoing studies
rTMS vs sham
currently not
reimbursed
very low quality of
the body of evidence
methodological
limitations
QoL outcomes and
patient satisfaction
neglected in the studies
Repetitive transcranial magnetic stimulation for treatment-resistant major depression
14 LBI-HTA | 2017
Conclusion
The body of evidence indicates that rTMS is generally safe and well-tolerated.
rTMS had a small short-term effect for improving depression in comparison
with sham, but follow-up studies did not show that the small effect will
con-tinue for longer periods. It remains unresolved if rTMS is as effective as
ECT, since no significant differences in remission and response rates where
found, and studies showed high heterogeneity at a low total sample size.
How-ever, rTMS patients had less, and not clinically relevant decreases in
depres-sion scores as compared to ECT patients.
Due to the low quality of evidence, new study results would potentially
in-fluence the effect estimate considerably. Additional research is needed to
support the finidings with high-quality evidence.
rTMS is safe and
well-tolerated, more
effective than sham,
unclear effectiveness
compared to ECT
further research
needed
Zusammenfassung
LBI-HTA | 2017
15
Zusammenfassung
Einleitung
Indikation und therapeutisches Ziel
Der Fokus dieses Berichts liegt in der Bewertung der transkraniellen
Mag-netstimulation zur Behandlung therapieresistenter Depression (TRD). Der
Bericht ging der Frage nach, ob repetitive transkranielle Magnetstimulation
(rTMS) im Vergleich zu einer Scheinintervention und im Vergleich zur
Stan-dardintervention der Elektrokonvulsionstherapie gleich wirksam bzw.
wirk-samer und gleich sicher, bzw. sicherer ist bei der Behandlung der TRD.
Unter TRD wird eine schwere Form der Depression verstanden (im
Engli-schen
Major Depression Disorder
, MDD), bei nach mindestens zwei Versuchen
verschiedener Antidepressiver Therapie (AD) sich keine Verbesserung
ein-stellt. Eine allgemeingültige Definition gibt es zurzeit jedoch noch nicht. Die
genaue Definition ab wann eine schwere Depression therapieresistent ist, ist
auch deshalb schwierig, da es keine Einigung gibt was als Therapieansprechen
gilt. In vielen Studien wird Therapieansprechen als eine mehr als 50
prozen-tige Verbesserung auf der Depression Skala eingestuft [1].
MDD wird derzeit mit den
Diagnostic Criteria for Major Depressive Disorder
and Depressive Episods
(DSM-IV-TR) diagnostiziert (Details in Appendix 4).
Alternative Verdachtsdiagnosen, wie bipolare Depression oder dysthymische
Störung, sollten aufgrund der unterschiedlichen Behandlungsmöglichkeiten
ausgeschlossen werden. Therapieresistente PatientInnen werden durch
Anam-nese und Krankengeschichte identifiziert.
Die Prävalenz der unipolaren TRD ist aufgrund der fehlenden international
anerkannter Definition nicht klar. Schätzungen zufolge sprechen 30-40 %
oder 50 % der PatientInnen – abhängig von der gewählten Definition des
The-rapieansprechens – nicht auf eine AD-Therapie an [3, 5, 44]. In Österreich
werden 120.000 bis 140.000 Patienten pro Jahr mit Depressionen
diagnosti-ziert, von denen nur 24.000 bis 36.000 ausreichend behandelt und Remission
erreicht wird [48]. Von den restlichen 84.000 bis 116.000 Patienten, werden
geschätzte 10-15 % (8.400 bis 17.400 Personen) nicht auf eine Therapie
an-sprechen.
Beschreibung der Technologie
Die repetitive transkranielle magnetische Stimulation (rTMS) ist eine
nicht-invasive Neurostimulation, die als eine Reihe Einzelimpulsen über eine
Mag-netspule auf den Kortex übertragen wird. Die typischsten technischen Daten
eines Einzelstimulus sind die Frequenzen (Hochfrequenz-Stimulation >1Hz
[5, 7] oder Niederfrequenz-Stimulation bei ≤ 1 Hz), Intensität,
Stimulations-dauer, Intervall zwischen den einzelnen Stimuli, und die Anzahl der Stimuli
pro Sitzung [7, 8].
Es gibt verschiedene Behandlungsprotokolle, wobei die FDA-basierten
Stan-dardparameter am weitesten verbreitet sind und für diesen Bericht
berück-sichtigt wurden: 10 magnetische Impulse pro Sekunde (Hz), 3.000 Impulse
pro Sitzung, 100 bis 120 % Intensität, Stimulationsdauer von 4 s mit
stimula-tionsfreiem Intervall von 26 s [9]. Die optimalen Einstellungen für die
Wirk-samkeit der rTMS sind allerdings nicht belegt.
Fragestellung
Definition TRD:
schwere Depression,
keine Verbesserung
durch verschiedene
AD Therapie
MDD = schwere
Depression,
nach DSM-IV TR
diagnostiziert
Prävalenz: nicht klar,
geschätzt: bis zu 50 %
der PatientInnen kein
Therapieansprechen
auf AD-Therapie
in Österreich:
140.000 PatientInnen
mit Depression,
circa 15 % TRD
rTMS: nicht-invasive
kranielle Stimulation
verschiedene Arten und
Intensitäten (niedrig
und hochfrequent
rTMS)
unterschiedliche
Behandlungsprotokolle,
meist:
FDA-Standardparameter
Repetitive transcranial magnetic stimulation for treatment-resistant major depression
16 LBI-HTA | 2017
rTMS ist für PatientInnen mit unipolarer, schwerer Depression (MDD)
in-diziert, die keine zufriedenstellende Verbesserung durch vorangegangene AD
Therapie hatten. Der erwartete Vorteil der rTMS gegenüber der Vergleich
Intervention der elektrokonvulsiven Therapie (ECT) ist die geringe
Invasi-vität, die ambulante Anwendung ohne Notwendigkeit einer Anästhesie und
Aufwachphase. Die PatientInnen können ihrer Tätigkeit im Anschluss der
Intervention ohne Einschränkungen nachgehen. Es wurden des Weiteren
kei-ne kognitiven Einschränkungen bei der Behandlung mit rTMS berichtet. Bei
ECT Sitzungen hingegen, können vorübergehende kognitive
Einschränkun-gen vorkommen, und umfassen Desorientierung beim Aufwachen, Amnesie,
Beeinträchtigung des Gedächtnisses während und nach der Behandlung mit
ECT. Allerdings sind diese Nebenwirkungen üblicherweise nur
vorüberge-hend mit Wiederherstellung der vollen kognitiven Funktionen innerhalb von
Wochen oder Monaten [4, 11].
Kontraindikationen für die Anwendung von rTMS sind PatientInnen mit
Me-tallimplantaten im Kopfbereich, implantierte Medizinprodukte
(Cochlea-Im-plantat, Herzschrittmacher, etc.), Schwangerschaft, erhöhter intrakranieller
Druck, Epilepsie bzw. erhöhte zerebrale Anfälligkeit für epileptische
Anfäl-le und allgemeine instabiAnfäl-le Komorbiditäten [7, 8, 10].
Methoden
Zur Beantwortung der Forschungsfrage wurde eine systematische
Literatur-suche und -analyse in zwei Phasen durchgeführt: als erster Schritt wurden
Sekundärstudien (z. B. HTA-Berichte und systematische Reviews/SRs)
an-hand ihrer Qualität, und ihrer Einschluss- und Ausschlusskriterien
bewer-tet. Zur Qualitätsbewertung der SRs wurde AMSTAR-Tool verwendet. Aus
insgesamt 20 vorliegenden SR wurde der Health Quality Ontario (HQO
Be-richt) [13] ausgewählt. In einem zweiten Schritt wurde eine ergänzende Suche
nach Primärstudien durchgeführt, die seit der Literatursuche des gewählten
HQO-Berichts [13] veröffentlicht wurden, und führte zum Einschluss zweier
randomisierter, kontrollierter Studien (RCT) [14, 15]. Die Studien verglichen
HF-rTMS mit der linken DLPFC mit einer Scheinintervention. Es wurden
keine weiteren Primärstudien gefunden, die rTMS mit ECT verglichen
ha-ben.
Klinische Wirksamkeit
Die Endpunkte Therapieansprechrate und Remissionsrate wurden für die
Beurteilung der Wirksamkeit als entscheidend definiert. Des Weiteren
wur-de eine durchschnittliche Verbesserung auf wur-der Depressionsskala (HDRS) als
wichtiger, jedoch nicht entscheidender Endpunkt herangezogen.
Sicherheit
Der entscheidende Endpunkt für die Beurteilung der Sicherheit war die
kog-nitive Einschränkung; wobei die Anzahl der Anfälle als wichtiger Endpunkt
eingestuft wurde.
rTMS indiziert für
PatientInnen mit MDD
ohne Verbesserung
bei AD Therapie
rTMS: wenig invasiv,
ambulant,
keine kognitiven
Einschränkungen
nach Behandlung
diverse
Kontraindikationen
entscheidende
Endpunkte Wirksamkeit
entscheidende
Entpunkte Sicherheit
Zusammenfassung
LBI-HTA | 2017
17
Ergebnisse
Verfügbare Evidenz
rTMS vs sham
Im HQO Bericht erfüllten 23 Studien die Einschlusskriterien, die durch zwei
zusätzliche RCTs aus der Primär Suche ergänzt wurden [14, 15]. Eines der
beiden RCTs [15] ist eine 6-Monats-Follow-up Studie einer im HQO-Bericht
bereits enthaltenen Studie [16]. Insgesamt wurden 1.180 Patienten in den
Stu-dien analysiert, 615 im aktiven rTMS-Arm und 565 im Scheinarm.
Die Einschlusskriterien der Studien unterschieden sich folgendermaßen:
Ausgangwerte auf der HDRS-17 Skala:
11 Studien: >25 HDRS-17 (schwere Depression)
14 Studien: 19 bis 24 (moderate Depression)
AD- Einnahme:
16 Studien: vorangegangener AD-Therapieversuch
mit zwei oder mehr AD
9 Studien: vorangegangener AD-Therapieversuch
mit einem oder mehr AD
17 Studien: rTMS unter AD- Therapie
8 Studien: keine AD Therapie während rTMS
Stimulationsparameter:
Frequenz (5 bis 20 Hz), Intensität (80 bis 120 %), Anzahl der
Sti-mulationen pro Sitzung (15 bis 75), die Stimulationsdauer (2 bis
10 Sekunden), Zwischenintervall (22 bis 58 Sekunden), Anzahl der
Impulse pro Sitzung von (800 bis 3.000) Gesamtzahl der Impulse
während der rTMS-Behandlung (8.000 bis 90.000).
Alle Studien verwendeten die
Figur 8
Spulen.
rTMS vs ECT
Der HQO-Bericht enthielt sechs Studien, die rTMS mit ECT verglichen. Die
meisten Studien wurden in den frühen 2000er Jahren durchgeführt. Die
Ge-samtzahl der Patienten betrug 266, 133 in jedem Arm.
Die Einschlusskriterien der Studien unterschieden sich folgendermaßen:
Ausgangwerte auf der HDRS-17 Skala:
24 bis 26 in der rTMS-Gruppe
25 bis 28 in der ECT-Gruppe
AD- Einnahme:
2 Studien: vorangegangener AD-Therapieversuch
mit zwei oder mehr AD
1 Studie: vorangegangener AD-Therapieversuch mit einem oder
mehr AD, bzw. 1 Studie berichtete AD-Therapieversuche in der
derzeitigen Episode
2 Studien: Einschluss von PatientInnen mit vorangegangener
ECT Therapie (keine Information zur AD Therapie)
2 Studien: rTMS bzw. ECT unter AD Therapie
2 Studien: medikamentenfrei
2 Studien: Therapie mit Lorazepam oder Clonazepam
verfügbare Evidenz:
SR mit 23 Studien,
2 RCTs
unterschiedliche
Einschlusskriterien der
verschiedenen Studien
in Bezug auf
Ausgangswerte,
AD-Einnahme und
Stimulationsparameter
verfügbare Evidenz:
SR mit 6 Studien,
266 PatientInnen,
133 pro Arm
unterschiedliche
Einschlusskriterien der
verschiedenen Studien
in Bezug auf
Ausgangswerte,
AD-Einnahme und
Stimulationsparameter
Repetitive transcranial magnetic stimulation for treatment-resistant major depression
18 LBI-HTA | 2017
Stimulationsparameter:
Frequenz (10Hz bzw 20 Hz), Intensität (90 bis 110 %), die Anzahl
der Stimulationen (20 bis 30-35), die Stimulationsdauer (2 bis 10 s),
Zwischeninterval (20 bis 55 s), die Impulse pro Sitzung (408 bis
2.500), Anzahl der Sitzungen (10 bis 20). Gesamtzahl der
geliefer-ten Impulse (4.080 bis 50.000).
Alle Studien verwendeten die
Figur 8
Spulen.
Klinische Wirksamkeit
rTMS vs sham
Im Durchschnitt verringerte rTMS die Punktezahl auf der Depressionsskala
um etwa 2.31 Punkte mehr als die Scheinintervention (95 % CI 1.19-3.43, p
<.001). Dies liegt allerding unter dem klinisch relevanten Schwellenwert von
3.5 Punkten.
Das gepoolte Risikoverhältnis für die Remissionsrate über 12 Studien betrug
2.16 (95 % CI 1.42-3.29, p = 0.0003). Das gepoolte Risiko-Verhältnis für die
Ansprechrate über 19 Studien betrug 1.82 (95 % CI 1.18-2.82, p = 0.0068).
In Bezug auf allgemeine und psychische Gesundheit, gemessen mit dem
SF-36 score, berichtete ein RCT [15] statistisch signifikanten Verbesserungen in
der rTMS Gruppe. Auch in Hinblick auf QoL fand die Studie statistisch
sig-nifikante Verbesserung in der rTMS Gruppe, gemessen mit dem
Q-LES-Q-Score.
rTMS vs ECT
Die gewichtete mittlere Differenz der Depressionswerte von der Baseline bis
zum Ende der Behandlung betrug -5.97 Punkte (95 % CI -11.00 – (-0.94), p =
0.020) zugunsten von ECT, und damit höher der klinisch relevante
Schwel-lenwert.
Das gepoolte Risikoverhältnis für die Remission betrug 1.44 (95 % CI
0.64-3.23, p = 0.375) am Ende der Behandlung zu Gunsten von ECT. Diese
Er-gebnisse sind allerdings nicht signifikant und die Studien wiesen ein hohes
Maß an Heterogenität auf (I
2= 69.1 %, p = 0.039).
Das gepoolte Risikoverhältnis Therapieansprechrate betrug 1.72 (95 % CI
0.95-3.11, p = 0.72). Wiederum waren diese Ergebnisse nicht signifikant, mit
einem hohen Maß an Heterogenität der Studien (I
2= 60.6 %, p = 0.079).
Die Selbstmordgedanken, gemessen sowohl mit BDI als auch HDRS Skala,
sanken signifikant stärker in der ECT Gruppe als in der rTMS Gruppe.
Sicherheit
rTMs vs sham
Die am häufigsten berichtete Nebenwirkung war Kopfschmerz. Die Rate der
Kopfschmerzen reichte von 0 bis 60 % in der rTMS-Gruppe und 0 bis 50 %
in der Scheingruppe. Krampfanfälle traten in keinen Studien auf, eine
tran-siente kognitive Beeinträchtigung trat bei fünf PatientInnen (16.7 %) in der
rTMS-Gruppe und einem Patienten (4.3 %) in der Scheingruppe ein.
rTMS vs ECT
Es wurden keine schwerwiegenden Nebenwirkungen berichtet. Bei
rTMS-PatientInnen waren Kopfschmerzen die häufigsten Nebenwirkungen,
ECT-PatientInnen berichten keine unerwünschten Ereignisse.
rTMS vs Sham
Verbesserung in der
Depressionsskala um
2,31 Punkte, klinisch
nicht relevant
Remissionsrate: RR 2.16
Ansprechrate: RR 1.82
zugunsten von rTMS
QoL: 1 RCT berichtete
signifikante
Verbesserungen
Verbesserung in der
Depressionsskala um
5,97 Punkte in
ECT Gruppe,
klinisch relevant
keine signifikanten
Unterschiede zw. rTMS
und ECT in Remissions-
und Ansprechraten
geringere
Selbstmord-gedanken bei ECT
keine schwerwiegenden
NW berichtet, häufigste
NW war Kopfschmerz
bei PatientInnen mit ECT
traten keine NW auf
Zusammenfassung
LBI-HTA | 2017
19
Laufende Studien
Es gibt vier laufende Studien zu rTMS im Vergleich zur Scheinstimulation,
aber keine laufenden Studien, die rTMS mit ECT vergleichen.
Kostenerstattung
Die Technologie wird in der Mehrheit der Länder, für die wir Informationen
zur Verfügung hatten, sowie in Österreich, nicht zurückerstattet.
Diskussion
Die Gesamtqualität des Beweismaterials ist sowohl für Schein- als auch für
ECT-Vergleichsstudien sehr gering.
Die methodischen Einschränkungen könnte die Empfehlung in Hinblick auf
die Robustheit der Wirksamkeitsergebnisse erheblich beeinflussen. Diese
Ein-schränkungen beinhalten variable Studienparameter
(rTMS-Behandlungspro-tokolle, die Definition der Remission, die Definition der TRD, Verwendung
als Mono- oder Add-On-Therapie), das Bias Risiko (ein hohes Risiko Bias dem
ECT-kontrollierte Studien auf Grund fehlender Verblindung), kleine
Patien-tInnen Fallzahlen (sowohl im Schein- als auch in der ECT-kontrollierten
Stu-die).
Lebensqualität und PatientInnen Zufriedenheit wären wünschenswerte
pri-mär Endpunkte für Studien an therapieresistenter Depression; diese wurden
jedoch nur von einer Studie berichtet. Des Weiteren fehlen Langzeitdaten zu
Wirkung von rTMS.
Empfehlung
Die Ergebnisse der Bewertung zeigen, dass rTMS im Allgemeinen sicher und
gut verträglich ist. rTMS hatte einen kurzfristigen Effekt auf die
Verbesse-rung der Depression im Vergleich zur Scheinintervention, der allerdings
kli-nisch nicht relevant sein könnte. Follow-up Studien konnten keinen
langan-haltenden Effekt von rTMS finden.
Die Wirksamkeit im Vergleich zu ECT zeigt einen Vorteil von ECT
gegen-über rTMS in Bezug auf die klinisch relevante Verbesserung auf der
Depres-sionsskala; jedoch gibt es keine signifikanten Unterschiede im Hinblick auf
Ansprechrate und Remissionsrate. Die Qualität der Studien ist sehr niedrig,
unter anderem bedingt durch die niedrige Fallzahl und hohe Heterogenität
der Studien.
Aufgrund dieser niedrigen Qualität der Evidenz könnten neue
Studiener-gebnisse die Effektschätzung erheblich beeinflussen. Weitere Studien, die
Langzeitdaten zu rTMS untersuchen, sind notwendig, um die tatsächliche
Wirksamkeit der Intervention zu bestätigen.
4 laufende Studien
zu rTMS vs Sham
derzeit nicht erstattet
sehr niedrige Qualität
der Evidenz
methodische
Einschränkungen
QoL-Ergebnisse
und PatientInnen
Zufriedenheit in den
Studien vernachlässigt
rTMS ist sicher und gut
verträglich, effektiver
als Scheinintervention
Wirksamkeit gegenüber
ECT unklar
neue Studien mit
Langzeitdaten von rTMS
nötig um Wirksamkeit
zu bestätigen
Scope
LBI-HTA | 2017
21
1
Scope
1.1
PICO question
Is repetitive transcranial magnetic stimulation (rTMS) in patients with
treat-ment-resistant major depression as effective as or more effective than and as
safe as or safer than sham stimulation or electroconvulsive therapy (ECT)?
1.2
Inclusion criteria
Inclusion criteria for relevant studies are summarized in Table 1-1.
Table 1-1: Inclusion criteria
Description Project scope
Population
Adult patients (>18 yrs) with major depressive disorder (MDD) as defined by DSM IV-TR or ICD-10, which is treatment resistant (IV-TRD) and characterized by:
syndrome of unipolar depression with or without psychotic features and
lack of clinically meaningful improvement despite the use of at least 2 antidepressant agents from different pharmacological classes with each antidepressant medication trial being adequate in terms of dose, duration, compliance, and tolerability
Intended use of technology: third- and subsequent-line treatment
MeSH terms: Major depressive disorder F03.600.300.375, Depressive disorder, treatment-resistant: F03.600.300.387
ICD-10 categories: F32 Depressive episode, F33 Recurrent depressive disorder
Rationale: population has been chosen based on information from the relevant published clinical guidelines [5, 7, 20-24] and amended following comments from external experts.Intervention
Repetitive transcranial magnetic stimulation (rTMS) as a therapeutic intervention in the acute phase
MeSH term: Transcranial Magnetic Stimulation E02.621.820
The following intervention will be considered:High-frequency (≥5 Hz) rTMS of the left dorsolateral prefrontal cortex (DLPFC) as
monotherapy
oradd-on therapy
Products to be considered:
MagStim: Magstim Rapid2, Super Rapid2 and Super Rapid2 Plus1
Magventure: MagVita TMS Therapy system, Magpro X100 Stimulator, Magpro R30 Stimulator
Neurostar: NeuroStar TMS therapy system
Mag & More: PowerMAG, Different versions: PowerMAG Clinical 30, PowerMAG Clinical 100, PowerMAG Research 30, PowerMAG Research 100
Neurosoft: Neuro-MS, Neuro-MS/DRationale: relevant published clinical guidelines [5, 21] issued level A recommendation for the use of high-frequency rTMS of the left DLPFC; for the use of low-frequency rTMS of the right DLPFC level B recommendation (probable effect) has been issued.
PIKO-Frage
Einschlusskriterien
für relevante Studien
Repetitive transcranial magnetic stimulation for treatment-resistant major depression
22 LBI-HTA | 2017
Description Project scope
Comparison
Sham stimulation (with antidepressant medication or no medication)
ECTRationale: Comparator has been chosen based on information from EUnetHTA guidelines [25-27] and relevant published clinical guidelines [5, 7, 20-24], in which ECT is recommended for TRD patients after two treatment failures as a nonpharmacological treatment option. Other somatic therapies are not yet well established.
Outcomes
Clinical endpoints:Clinical effectiveness
Change in depression score (measured on one of the following scales: HDRS/HAMD, MADRS, BDI or QIDS)
Response rate (≥ 50% reduction in the depression scores)
Remission rate (HAMD score <7, MADRS score <7, QUIDS score <5)
Patient satisfaction
QoL
Relapse rateSafety:
Serious adverse device effect (SADE)
Seizure
Transient impairment of working memory
Induced currents in implanted devices
Adverse device effect (ADE):
Syncope (fainting)
Scalp discomfort or pain
Transient induction of hypomania
Transient hearing loss
Headache
Facial twitching
Vertigo
Device-related insomnia/drowsiness
Mild confusion
Other AEsRationale: outcomes have been chosen based on information from relevant published clinical guidelines [5, 7, 20-24] and EUnetHTA guidelines [25-27].
Abbreviations:
AEs adverse events, BDI Beck Depression Inventory, HDRS/HAMD Hamilton Depression Rating Scale, MADRS Montgomery-Asberg Depression Rating Scale, QIDS Quick Inventory of Depressive Symptomatology, QoL quality of lifeLBI-HTA| 2017 23
2
Methods and evidence included
2.1
Research questions
Element ID Description and technical characteristics of the technology B0001 What are rTMS, sham stimulation and ECT?
A0020 For which indications rTMS received marketing authorisation or CE marking?
B0002 What is the claimed benefit of rTMS in relation to sham stimulation and ECT?
B0003 What is the phase of development and implementation of rTMS and ECT?
B0004 Who administers rTMS and ECT and in what context and level of care is it provided?
B0008 What kind of special premises are needed to use rTMS and ECT? B0009 What equipment and supplies are needed to use rTMS and ECT? A0021 What is the reimbursement status of rTMS?
Element ID Health problem and current use of the technology A0002 What is treatment-resistant major depressive disorder? A0003 What are the known risk factors for treatment-resistant major
depressive disorder?
A0004 What is the natural course of treatment-resistant major depressive disorder?
A0005 What are the symptoms and the burden of treatment-resistant major depressive disorder for the patient?
A0006 What are the consequences of treatment-resistant major depressive disorder for the society?
A0024 How is treatment-resistant major depressive disorder currently diagnosed according to published guidelines and in practice? A0025 How is treatment-resistant major depressive disorder currently
managed according to published guidelines and in practice? A0007 What is the target population in this assessment?
A0023 How many people belong to the target population? A0011 How much is rTMS utilised?
Element ID Clinical effectiveness
D0001 What is the expected beneficial effect of rTMS on mortality? D0005 How does rTMS affect symptoms and findings (severity,
frequency) of treatment-resistant major depressive disorder? D0006 How does rTMS affect progression (or recurrence) of
treatment-resistant major depressive disorder? D0011 What is the effect of rTMS on patients’ body functions? D0016 How does the use of rTMS affect activities of daily living? D0012 What is the effect of rTMS on generic health-related quality of life? D0013 What is the effect of rTMS on disease-specific quality of life? D0017 Were patients satisfied with rTMS?
Repetitive transcranial magnetic stimulation for treatment-resistant major depression
24 LBI-HTA | 2017
Element ID Safety
C0008 How safe is rTMS in relation to sham stimulation and ECT? C0002 Are the harms related to dosage or frequency of applying rTMS? C0005 What are the susceptible patient groups that are more likely
to be harmed through the use of rTMS?
C0007 Are rTMS, sham stimulation and ECT associated with user-dependent harms?
B0010 What kind of data/records and/or registry is needed to monitor the use of rTMS, sham stimulation and ECT?
2.2
Source of assessment elements
The selection of assessment elements is based on the HTA Core Model
Ap-plication for Rapid Relative Effectiveness (REA) Assessments (4.2). The
se-lected issues (generic questions) are translated into actual research questions
(answerable questions).
2.3
Search
Detailed tables on search strategy are included in
Appendix 1
.
Given the extensive body of evidence (randomized controlled trials/RCTs,
sys-tematic reviews/SRs and meta-analysis/MAs) the syssys-tematic literature search
and analysis of the studies was performed in two phases: secondary studies
(i.e. HTA reports and SRs) were screened as a first step and evaluated on the
basis of their scope, inclusion and exclusion criteria, and quality. Primary
studies were considered for inclusion in the second step. We did not apply
any restrictions on language.
The following sources of information were used in the first search:
Cochrane Library,
Centre for Research and Dissemination (CRD),
Embase,
Medline,
PsychInfo,
Handsearch (in reference list of relevant studies).
Secondary studies were retrieved in full-text version. HTA reports and SRs
were extracted and tabulated in ascending chronological order. Only the most
recent reports (published in 2012-2016) were discussed qualitatively. SRs were
assessed according to year of publication, time range, scope, and population
to identify the most recent review that overlapped with the scope of the
pre-sent assessment. The AMSTAR tool was used for quality assessment of SRs.
Details can be found in Table A-3 in Appendix 1. The Health Quality
Ontar-io (HQO) HTA report [13] was selected for update.
Bericht folgt
HTA Core Model für REA
Literatursuche in
2 Schritten:
1. Suche nach sekundär
Studien (HTA Berichte
und SR) in
5 Datenbanken
HTA Berichte und SRs
von 2012-2016
qualitative Bewertung
Methods and evidence included
LBI-HTA | 2017
25
To identify further, more recent, primary studies fulfilling the inclusion
cri-teria of the present assessment, a literature search for RCTs published since
the literature search of the chosen HTA report [13] was performed. The time
period of the search was limited to November 2014 to January 2017. The
fol-lowing sources of information were used:
Cochrane Library,
Embase,
Medline,
PsychInfo,
Handsearch (in reference list of relevant studies)
In addition, the following clinical trials databases were searched to identify
ongoing studies on the rTMS in major depression:
ClincalTrials.gov
EU Clinical Trials Register
International Clinical Trials Registry Platform (ICTRP).
Clinical Practice Guidelines (CPGs) were also searched in the UptoDate
da-tabase, through handsearch and consultation with clinical experts.
2. Suche nach
zusätzlichen primär
Studien (RCTs) in
4 Datenbanken
Suche nach laufenden
Studien zu rTMS
Repetitive transcranial magnetic stimulation for treatment-resistant major depression
26 LBI-HTA | 2017
2.4
Study selection
2.4.1
Selection of systematic reviews
Figure 2-1:
Flow chart for selection of systematic reviews
The author (LBI-HTA) and the co-author (OSTEBA) screened and selected
studies independently from each other. The author checked the
discrepan-cies. Any disagreements were resolved by consensus.
The search yielded 669 records and after deduplication, 326 records
re-mained for screening. The reference list was screened by title and abstract to
identify potentially relevant studies. A cross-reference search identified one
further study.
Literaturauswahl
insgesamt
326 Publikationen
identifiziert
Records identified through database searching (n = 669)
Scr
ee
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ng
Incl
ud
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ib
ility
Id
en
tif
ic
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Additional records identifiedthrough other sources (n = 1)
Records after duplicates removed (n = 327)
Records screened (n = 327)
Records excluded (n = 297) Full-text articles assessed
for eligibility (n = 30)
Full-text articles excluded, with reasons
(n = 10) Exclusion criteria are e.g.:
Background literature (n=4)
Other population (n = 0)
Not available (n = 3)
Other intervention (deep rTMS) (n = 2)
Not reporting the outcomes of interest (n = 1)Studies included in qualitative synthesis (n = 20)
rTMS vs sham SRs (n = 9) rTMS vs ECT SRs (n = 6) rTMS vs sham and ECT SRs (n = 5)
Studies included in quantitative synthesis (n = 1)
Methods and evidence included
LBI-HTA | 2017
27
A total of 20 SRs were selected that fulfilled our inclusion criteria. 14 studies
had only one comparator each: nine compared rTMS with sham stimulation
and six compared active stimulation with ECT. Five SRs included both
com-parators. Seven SRs included various types of rTMS (HF, LF, mixed
frequen-cies) applied to different sites. From these we considered only the HF-rTMS
to the left DLPFC parts of the SR and extracted data regarding that
(num-ber of patients, studies included, scope of the assessment, inclusion criteria
used). We assessed the quality of the SRs with the AMSTAR tool. The HQO
report [13] was selected for update within the present assessment on the
ba-sis of the year of publication, time range, scope, population, intervention,
out-comes measured, comparators, and the AMSTAR score.
2.4.2
Selection of primary studies
Figure 2-2: Flow chart for selection of primary studies
20 SRs von denen
14 rTMS mit sham und
6 rTMS mit ECT, und
5 Studien beide
Interventionen mit
rTMS verglichen
Qualität mittels
AMSTAR bewertet
Records identified through database searching (n = 849)
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Additional records identifiedthrough other sources (n = 0)
Records after duplicates removed (n = 521)
Records screened (n = 521)
Records excluded (n = 505) Full-text articles assessed
for eligibility (n = 16)
Full-text articles excluded, with reasons
(n = 14) Exclusion criteria are e.g.:
Other intervention (maintenance therapy or targeting other than the left site) (n = 2)
Publication before the search period of interest (n = 9)
Study design non-RCT (n = 2)
Only follow-up data (n = 1) Studies included in qualitative synthesis(n = 2) rTMS vs sham (n = 2)
rTMS vs ECT (n= 0)
Studies included in quantitative synthesis (n = 2)
Repetitive transcranial magnetic stimulation for treatment-resistant major depression
28 LBI-HTA | 2017
Primary studies in the period November 2014 – January 2017 were screened
to identify new evidence. The search yielded 849 records, after deduplication
521 records remained for screening. A hand search identified no further
stud-ies. In total, two studies [14, 15] were selected that fulfilled our inclusion
cri-teria and included within the present assessment. The two studies compared
HF-rTMS to the left DLPFC with sham. No studies were found that
com-pared active stimulation with ECT. Additionally, as the selected SR did not
define QoL as an efficacy outcome and the included primary studies did not
report on it, we also screened primary studies of the last 5 years (2012-2016).
We tried to find those studies that might have been excluded from the selected
SR in case they did not report on the primary outcomes defined in the SR.
2.4.3
Selection of guidelines
We identified guidelines via systematic search and hand search. The
guide-lines of the main scientific and professional organizations (APA, CANMAT,
IFCN, RAZCP, and WSFBP) and the guidelines applicable by professional
organizations of the author’s (Austria, DGPPN) and co-author’s (Spain,
AVALIA-t) country of origin were selected to be included in the overview of
available guidelines.
2.5
Quality rating of studies
AMSTAR was used to assess the quality of SRs and the Cochrane risk of bias
assessment approach was used to assess RCTs (ACROBAT-NRSi tool),
ac-cording to the EUnetHTA Guidelines on Therapeutic medical devices [25].
For the assessment of the strength of evidence, the “Grading of
Recommen-dations, Assessment, Development and Evaluation” – GRADE approach was
used. These steps were performed by the author independently from the
co-author(s). Any disagreements were resolved by consensus. The preliminary
classification of the importance of the outcomes (GRADE specifies three
cat-egories of outcomes according to their importance for decision-making:
cru-cial, important, and of limited importance) was done in consensus by the
au-thors.
For Description and Technical Characteristics of Technology (TEC) and
Health Problem and Current Use of the Technology (CUR) domains, no
qual-ity assessment tool was used, but multiple sources were used in order to
val-idate individual, possibly biased, sources. Descriptive analysis of different
information sources was performed. The completed EUnetHTA submission
file from the manufacturers was used as a starting point. The AGREE II tool
was used for the quality rating of guidelines. Two authors scored the
guide-lines independently from each other, disagreements were solved by consensus.
insgesamt
521 Primärstudien
identifiziert
Leitlinien relevanter
Organisationen,
im besonderen aus
Österreich und Spanien
AMSTAR zur Bewertung
der Qualität der
sekundär Studien
Zusammenfassung der
Ergebnisse mit GRADE
AGREE II zur
Bewertung der
Qualität der Leitlinien
Methods and evidence included
LBI-HTA | 2017
29
2.6
Statistical-analysis
We conducted a meta-analysis of the pooled results in the R environment [28]
using the package ‘‘meta’’ [29]. The HQO report used a random effects model
for the meta-analysis; we also chose this model in our calculations. The degree
of statistical heterogeneity among studies was assessed using the I-squared
(I
2) and tau-squared statistics.
We calculated changes in depression scores measured by Hamilton Rating
Scale for Depression from baseline to the end of treatment and conducted a
meta-analysis on the mean changes in scores for the rTMS treatment and
con-trol groups. We calculated the effect size as the difference between the means
of the two groups divided by the standard deviation (SD), a statistical
meth-od known as standardized mean difference (SMD) using Cohen’s methmeth-od.
We used Cohen’s conventional definition of small, medium, and large effect
size as 0.2, 0.5, and 0.8, respectively. Pooled effect sizes for depression scores
were calculated in the HQO report using weighted mean difference, the mean